The MODY-associated TALK-1 L114P mutation causes islet α-cell overactivity and β-cell inactivity resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

Abstract

AbstractA gain-of-function mutation in the TALK-1 K+channel (p.L114P) associated with maturity-onset diabetes of the young (MODY) was recently reported in two distinct families. TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion (GSIS).KCNK16, the gene that encodes TALK-1, is the most abundant and β-cell– restricted K+channel transcript; polymorphisms in theKCNK16locus are also associated with an increased risk of type-2 diabetes. To investigate the impact of TALK-1-L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing theKcnk16L114P mutation was generated. Heterozygous and homozygousKcnk16L114P mice exhibit increased neonatal lethality in the C57BL/6J and the mixed C57BL/6J:CD-1(ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygousKcnk16L114P neonates due to lack of GSIS and can be reduced with insulin treatment. TALK-1-L114P drastically increased whole-cell β-cell K+currents resulting in blunted glucose-stimulated Ca2+entry and loss of glucose-induced Ca2+oscillations. Thus, adultKcnk16L114P mice have reduced GSIS and plasma insulin levels, which significantly impaired glucose homeostasis. Taken together, this study determined that the MODY-associated TALK-1-L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by altering islet hormone secretion during development. These data strongly suggest that TALK-1 is an islet-restricted target for the treatment of diabetes.